Assessment of annexin A5 and annexin A2 levels as biomarkers for pre-eclampsia: A pilot study

https://doi.org/10.1016/j.preghy.2017.03.006Get rights and content

Highlights

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    Serum annexin A2 is significantly reduced in women with pre-eclampsia (total and severe cases) compared to those with normal pregnancy.

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    The ROC analysis of annexin A2 level for the prediction of development of PE showed an area under the curve of 0.64 (P = 0.029), and the best cut-off value was 0.89 ng/ml with a sensitivity of 70.0% and a specificity of 70.0%.

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    High serum annexin A2, elevated blood pressure, proteinuria and lower platelet count are associated with significantly higher risk to develop PE.

Abstract

Deficient anticoagulant activity of annexin A5 and deficient profibrinolytic activity of annexin A2 have been linked to increased risk of thrombotic events. Placental dysfunction due to fibrin deposition/microthrombi has been implicated in the pathogenesis of pre-eclampsia (PE). In this study, we aimed to assess serum levels of annexin A5 and annexin A2 in a cohort of PE patients and investigate their role as biomarkers for the development of the disease. We examined 80 women in total; 40 healthy pregnant women and 40 pregnant women with PE after 20 weeks of pregnancy. Women were subjected to full clinical assessment, ultrasonography, and laboratory testing including complete blood picture, liver and kidney function tests and assessment of serum and urine proteins. Annexin A5 and annexin A2 were analyzed using enzyme-linked immunosorbent assay. The study showed serum annexin A2 but not annexin A5 was significantly reduced (P = 0.029) in women with PE (total and severe cases) compared to those with normal pregnancy. The ROC analysis of annexin A2 level for the prediction of development of PE showed an area under the curve of 0.64 (P = 0.029), and the best cut-off value was 0.89 ng/ml with a sensitivity of 70.0% and a specificity of 70.0%. Univariate analysis showed annexin A2 of <0.89 ng/ml, proteinuria, lower platelet count and higher BP were associated with significantly higher risk to develop PE. Based on this pilot study, serum annexin A2 levels may be a useful biomarker for pre-eclampsia. However, a larger study is required before a final conclusion is made.

Introduction

Pre-eclampsia (PE) is a multifactorial disease affecting 2–8% of pregnancies and remains a leading cause for maternal and perinatal morbidity and mortality worldwide [1]. The exact mechanisms, which lead to PE, are not clear but several factors appear to help predict who will develop this disease. These factors include family history, age and parity. The primary established pathophysiology in PE resides in the abnormal trophoblastic implantation with reduced placental perfusion. The secondary pathology appears to be endothelial cell injury, oxidative stress and activation of the coagulation system [2]. Placental dysfunction has been reported to play a major role in the pathogenesis of PE as well as modulate the disease outcome. Fibrin deposition and microthrombi are known histopathologic alterations in placental dysfunction in preeclampsia [2], [3]. The mechanisms of these thrombotic changes are not fully understood. Most studies have focused on the clotting activities and little is known about the changes in the fibrinolytic system in pregnancies complicated with this disease [4], [5].

Annexin A5 belongs to the family of annexins, which are highly homologous phospholipid binding proteins. It can be found in various cell types such as platelets and endothelial cells and has also been detected in placental villi [6]. It is an anionic phospholipid-binding protein with potent anticoagulant activity. It inhibits prothrombin activation and is able to prevent thrombus formation under normal venous and arterial blood flow conditions [7]. Several studies have suggested that annexin A5 may protect the syncytial surface against clot formation [8], [9] and lower amounts of annexin A5 expression on trophoblasts has been noted in pre-eclamptic patients compared to healthy pregnant [10], [11], [12].

Annexin A2, a member of annexin family, is a calcium-regulated phospholipid binding protein which is expressed on a number of cell types including endothelial cells, macrophages, a variety of tumor cells, and also on the brush-border membrane of placental syncytiotrophoblast [13], [14]. It is a cell surface co-receptor for plasminogen and its activator; tPA and its binding promotes significantly cell surface plasmin generation [15]. In peripheral maternal blood, there was an association between low levels of annexin A2 and PE and low fetal birth weight. Levels of expression of annexin A2 were inversely correlated with the severity of placental thrombin generation [5].

Few studies have investigated the role of annexin A5 [11], [12], [16] and annexin A2 [5], [17] in pre-eclampsia. These studies have either explored one or the other. Moreover; they mostly focused on the local expression of these proteins in the placenta tissue rather than examining blood levels of these proteins. In the current study, the role of serum annexins A5 & A2 as biomarkers of PE is carefully examined.

Section snippets

Patients’ recruitment and classification

This pilot study examined a total of 80 women; 40 were healthy pregnant women with an average age of 27 years (range:19–37) and 40 women diagnosed with pre-eclampsia (after 20 weeks of gestation) with an average age of 28 years (range:18–43). The patients were selected from the outpatient clinic of Obstetric and Gynecological Department in Mansoura University Hospital. Clinical characteristics of the study population are shown in Table 1. Diagnosis of pre-eclampsia and determination of severity

Results

The clinical characteristics of patients’ groups compared with controls are summarized in Table 1. The patients’ ages ranged from 18–43 years compared with an age-matched control group (ages ranged from 19–37 years). There were no significant differences in maternal age, gravidity and parity between total patients and controls. There were significant differences in mean gestational age between total patients and controls and between each of the mild and severe PE in comparison with control group (

Discussion

Dysfunction of the placenta has been considered to play an important role in the pathogenesis of PE as well as in the prognosis of the disease. One of the most common histopathologic dysfunctional alterations seen in the placenta of PE patients are various grades of thrombosis and placental infarctions [3], [4], but the mechanism behind these microthrombi is not fully understood [5]. While several factors such as family history, age and parity appear to help predict who will develop the

Conclusion

Based on the data presented in this study, annexin A2 can potentially predict the development of pre-eclampsia. The low annexin A2 levels (<0.89 ng/ml) together with higher blood pressure and proteinuria constitute a higher risk to develop pre-eclampsia. However, the relatively small number of patients limit a validated generalizable conclusion. Further studies with larger sample size need to be conducted to prove/ improve the utility of annexin A2 as predictor/ biomarker for pre-eclampsia.

Author contributions

Marwa Abd El-Latif & Hanan Azzam: designed and conducted research, analyzed data and drafted manuscript. Osama Warda recruited patients and provided clinical data. Solafa El-Sharawy & Hayam Ghoneim designed and supervised research. Maha Othman contributed intellectually to the study and wrote manuscript.

Conflict of interest

The authors have no competing interests to declare.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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